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The mechanism of body and organ size control is an unsolved puzzle. Initially characterized in Drosophila melanogaster, the Salvador/Warts/Hippo (Hippo) signalling pathway, highly conserved throughout evolution, defines a novel signalling cascade regulating cell contact inhibition, organ size control, cell growth, proliferation, apoptosis, and cancer development in mammals. The upstream regulation of this pathway has been less well defined than the core kinase cassette. Previously Willin/FRMD6 has been proposed as the human orthologue of Expanded and, to date, little is known about the functional role of Willin in mammalian cells. My study elucidated the mechanism by which Willin antagonizes the transcriptional co-activator YAP. In MCF10A cells, Willin ectopic expression antagonizes YAP-induced epithelial-mesenchymal phenotypes via YAP Ser127 phosphorylation site. Loss of Willin expression attenuates MST1/2, LATS1, and YAP phosphorylation promoting YAP's oncogenic transformation activity in vitro, as analysed by its ability to display epithelial-to-mesenchymal transition (EMT) features. These biological outputs are YAP dependent. These data support the involvement of Willin in the regulation of the mammalian Hippo signalling activity by activating the core Hippo pathway kinase cassette. KIBRA has been shown to function as an upstream member of the Hippo pathway by influencing the phosphorylation of LATS and YAP, but the functional consequences of these biochemical changes have not been previously addressed. I showed that in MCF10A cells, loss of KIBRA expression displays EMT features, which are concomitant with decreased LATS and YAP phosphorylation, but not MST1/2. In addition, ectopic KIBRA expression antagonizes YAP via the Ser 127 phosphorylation site and I showed that KIBRA, Willin and Merlin differentially regulate genes controlled by YAP. Willin/FRMD6 was first identified in rat sciatic nerve, which is composed of Schwann cells and fibroblasts. To elucidate the function of Willin in the mammalian sciatic nerve, I showed that Willin is predominantly expressed in fibroblasts and that its expression activates the Hippo signalling cascade and induces YAP translocation from the nucleus to the cytoplasm. In addition within these cells, although it inhibits cellular proliferation, Willin expression induces a quicker directional migration towards scratch closure and an increased expression of factors linked to nerve regeneration. These evidence show that Willin modulates sciatic nerve fibroblast activity, indicating that Willin may have a potential role in the regeneration of the peripheral nervous system.

TAZ (Transcriptional co-activator with PDZ-binding motif) is a WW-domain containing protein recently identified as a downstream component of the Hippo tumor suppressor pathway and mediator of biologically important processes (mesenchymal stem cell differentiation, embryonic stem cell renewal, mechanotransduction). Recently, loss of LATS1/2, a negative regulator of TAZ, has been observed in ~50% of breast cancers. However, whether and how TAZ is also involved in breast cancer has not been investigated. Therefore, this study explores the cellular functions of TAZ in breast cancer and the underlying molecular mechanisms. The cellular functions of TAZ were investigated using overexpression studies in an immortalized mammary epithelial cell line (MCF10A). Compared to control vector-only expressing cells (MCF10A-WPI) TAZ overexpression (MCF10A-TAZ) promotes enhanced cell proliferation, cell migration and cell-ECM adhesion, induces transformation and the epithelial-mesenchymal transition, and confers resistance to chemotherapeutics (paclitaxel, cisplatin). Together, these findings strongly suggest TAZ functions as an oncogene in the development, progression and drug resistance of breast cancer. As a transcriptional co-activator, TAZ likely mediates these cellular functions through the transcriptional activation of downstream genes. By screening a 44K human genome microarray we have identified and characterized Cyr61 and CTGF, mediators of paclitaxel resistance, and BMP4, a regulator of cell migration. Through stable shRNA-mediated knockdown, we show that loss of Cyr61/CTGF expression in MCF10A-TAZ cells can rescue TAZ-induced paclitaxel resistance. Similarly, shRNA-mediated knockdown of BMP4 can significantly attenuate TAZ-induced cell migration. Therefore, these findings demonstrate that Cyr61/CTGF and BMP4 are functionally significant mediators of TAZ-induced paclitaxel resistance and cell migration, respectively. The clinical relevance of our in vitro findings were also validated by immunohistochemistry using tissue microarrays containing human breast cancer samples. TAZ levels were highly expressed in 66.6% of clinical samples further suggesting TAZ may be an important oncogene in breast cancer. Our study has characterized TAZ as an oncogene in breast cancer and elucidated two novel mechanisms underlying paclitaxel resistance and cell migration. These findings highlight the importance of TAZ during the development, progression and drug resistance of breast cancers and the potential use of TAZ as a therapeutic target to treat TAZ-expressing breast cancers. / Thesis (Ph.D, Pathology & Molecular Medicine) -- Queen's University, 2013-08-01 23:59:08.68

Thesis advisor: Boyd Coolman / This study considers the development of Augustine's early soteriology in the years leading up to and including his writing of Confessions. Central to that inquiry is a treatment of his increasing use of the term humilitas. Yet that inquiry necessitates a broader account of the fallen soul and its healing by the Incarnate Savior. The result is a mostly chronological survey that shows Augustine developing clearer connections between his soteriology, Christology, and sacramental theology. / Thesis (PhD) — Boston College, 2018. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Theology.

Pancreatic ductal adenocarcinomas (PDACs) are highly aggressive malignancies, associated with poor clinical prognosis and limited therapeutic options. The KRAS oncogene is mutated in over 90% of PDACs and plays a pivotal role in tumor progression. Global gene expression profiling of PDAC reveals 3-4 major molecular subtypes with distinct phenotypic traits and pharmacological vulnerabilities, including variations in oncogenic KRAS pathway dependencies. PDAC cell lines of the aberrantly differentiated endocrine exocrine (ADEX) subtype are robustly KRAS-dependent for survival. The KRAS gene is located on chromosome 12p11-12p12, a region amplified in 5-10% of primary PDACs. Within this amplicon, we identified co-amplification of KRAS with the STK38L gene in a subset of primary human PDACs and PDAC cell lines. This provided rationale to determine whether PDAC cell lines are dependent on STK38L expression for proliferation and viability. STK38L (also known as NDR2) encodes a nuclear Dbf2-related (NDR) serine/threonine kinase, which shares homology with Hippo pathway LATS1/2 kinases. We show that STK38L expression levels are elevated in a subset of primary PDACs and PDAC cell lines that display ADEX subtype characteristics, including overexpression of mutant KRAS. RNAi-mediated depletion of STK38L in a subset of ADEX subtype cell lines results in decreased cellular proliferation and increased apoptotic cell death. Concomitant with cytostatic and cytotoxic effects, STK38L depletion causes increased expression of the LATS2 kinase and the cell cycle regulator p21. LATS2 depletion partially rescues the cell proliferation and viability effects of STK38L depletion. Lastly, high STK38L mRNA expression is associated with worse patient prognosis compared to low STK38L expression in PDACs. Taken together, our study uncovers STK38L as a candidate, targetable vulnerability in a subset of molecularly defined PDACs. / 2019-11-01T00:00:00Z

Trata-se de uma dissertação sobre o pensamento filosófico de Agostinho de Hipona em relação à beleza do discurso e à utilidade da retórica e da eloqüência, temas que aparecem no livro IV do De doctrina christiana (Da instrução cristã) e, por isso, dentro da reflexão sobre o ideal de uma educação tipicamente cristã. Na Antigüidade, embora a eloqüência estivesse intrinsecamente ligada à arte retórica, esta questão, para Agostinho, deve ser tratada em conexão com algumas orientações da filosofia moral e da teologia cristãs, situadas para além da técnica. Em comparação com o antigo ideal oratório romano, sobretudo o ciceroniano, a maior importância conferida por Agostinho à Bíblia cristã, isto é, à sabedoria e à moral dos autores bíblicos, traz novos significados para o termo \'eloqüência\'. Além disso, o aprendizado oratório, que se alicerçava na doutrina e no hábito, é dessa vez resumido e transmitido por Agostinho segundo um método radical de imitação, cujos modelos passam a ser os escritores bíblicos e eclesiásticos, aqueles inspirados por Deus e gratificados com a união da eloqüência à sabedoria. / This dissertation is about the philosophical thinking of Augustine of Hippo in relation to the beauty of speech and the usefulness of rhetoric and eloquence, themes that appear in Book IV of De doctrina christiana (On Christian Teaching) and therefore within the reflection on the ideal of education typically Christian. In Antiquity, although the eloquence was intrinsically linked to the rhetorical art, this issue, for Augustine, it must be treated in connection with some directions of Christian moral philosophy and theology, located beyond the technique. In comparison to the antique ideal of Roman oratory, especially the Ciceronian, the greater importance given by Augustine to the Christian Bible, that is, to the wisdom and morality of the biblical authors, bring new meaning to the term \'eloquence\'. Moreover, the learning of oratory, which was based on the doctrine and habit, this time is summed up by Augustine and transmitted according to a radical method of imitation, whose models have to be the biblical and ecclesiastical writers, those inspired by God and rewarded with union between eloquence and wisdom.

Thesis (doctoral), Universität Regensburg, 1979. / Bibliographie : p. 405-413. Index.

This thesis explores the factors controlling the distribution of black carbon (BC) in the atmosphere/troposphere and its implications for climate forcing. BC is of great climate interest because of its warming potential. Estimates of BC climate forcing have large uncertainty, in part due to poor knowledge of the distribution of BC in the atmosphere. This dissertation first examines the factors controlling the sources of BC in the Arctic in winter and spring using a global chemical transport model (GEOS-Chem). Emission inventories of BC and wet scavenging of aerosols in the model are updated to reproduce observed atmospheric concentrations of BC as well as observed snow BC content in the Arctic in winter-spring. The simulation shows a dominant contribution of fuel (fossil fuel and biofuel) combustion to BC in Arctic spring. Arctic snow BC content is dominated by fuel combustion sources in winter, but has equal contributions from open fires and fuel combustion in spring. The estimated decrease in Arctic snow albedo due to BC deposition in spring is 0.6%, resulting in a regional surface radiative forcing of 1.2 W m-2. The dissertation then extends the evaluation of the BC simulation to the global scale using aircraft observations over source regions, continental outflow and remote regions and ground-based measurements. The observed low BC concentrations over the remote oceans imply more efficient BC removal than is currently implemented in models. The simulation that has total BC emissions of 6.5 Tg C a-1 and a mean tropospheric lifetime of 4.2 days for 2009 (vs. 6.8 &plusmn 1.8 days for the AeroCom models) captures the principal features of observed BC. The simulation estimates a global mean BC absorbing aerosol optical depth of 0.0017 and a top-of-atmosphere direct radiative forcing (DRF) of 0.19 W m-2, with a range of 0.17-0.31 W m-2 based on uncertainties in the BC atmospheric distribution. The DRF is lower than previous estimates, which could be biased high because of excessive BC concentrations over the oceans and in the free troposphere. / Engineering and Applied Sciences

In the present study, through a close reading of the Confessions , the author explores the concept of love in Saint Augustine as it pertains to the two possibilities of man, being towards the creation and being towards the Creator. He distinguishes two kinds of love corresponding to each one of these possibilities, love of the world (cupiditas) and love of God (caritas), and proceeds to analyze these loves. The main argument of the thesis is that these loves disclose the world to man in two opposed manners. The author argues that cupiditas seeks to find satisfaction in the creation and discloses it as an end in itself, whereas caritas loves the world for the sake of God and discloses it as a means to attaining God.

St. Augustine believed that we are created to aspire to a perfection that aligns our relationships in such a way that we function out of a sense of respect for ourselves and the universe in which we live. In so doing we explore the possibilities of creativity and happiness. His thinking moved from the context of classical Greek thought into a Christian one. By living and recording the dilemma of being unable to act as his intellect mandated, he developed an innovative concept of will. He believed that we are motivated to act through our loves but we have a divided will that can only move towards integration if we love correctly. This necessitates an inward journey. / The thesis of this paper is that if one subscribes to Augustine's beliefs there are serious implications for education. The following authors are cited to develop these implications in a modern philosophical and educational setting: Charles Taylor, Iris Murdoch, Israel Scheffler and Bob Samples. Finally, a brief resume of relevant teaching approaches and materials is offered.